Luminal or tubular grafts are useful for an extensive number of medical applications.
A. Small-Diameter Vascular Grafts
Vascular grafts, especially, are in high demand due to recent expansions in the field. A major problem in vascular surgery is how to effectively supply blood to organs and tissues whose blood vessels are inadequate either through congenital defects or acquired disorders such as trauma, arteriosclerosis or other diseases.
To date, the search for the ideal blood vessel substitute has focused on biological tissues and synthetics. Initially, arterial homografts (human arteries) were used to restore vascular continuity; however, limited supply, inadequate sizes, development of aneurysms and arteriosclerosis necessitated the search for a better substitute. Additional substitutes that have been employed include autologous blood vessels, vessels of xenogenic origin, as well as vascular prostheses typically made from Dacron or polytetrafluoroethylene.
Despite intensive efforts to improve the nature of blood vessel substitutes, many problems with conventional substitutes remain. For example, conventional vascular grafts typically suffer from high failure rates related to (a) occlusion by thrombosis or kinking, or due to an anastomotic or intimal and subintimal hyperplasia (exuberant cell growth at the interface between the native vessel and graft); (b) a decreasing caliber of the blood vessel substitute; (c) resulting infection; (d) biological failure or degradation; and/or (e) aneurysm formation. Other problems may involve compliance mismatches between the host vessel and a synthetic vascular prosthesis, which may result in anastomotic rupture, stimulated exuberant cell responses, and/or disturbed flow patterns and increased stresses leading to graft failure.
Vascular grafts can be used in the treatment of numerous types of medical conditions, spanning a broad range of biological tissues. For example, and as described in further detail below, vascular grafts can be employed in treating cardiovascular disease, obtaining vascular access for hemodialysis, as well as in nerve regeneration procedures. Unfortunately, conventional knowledge has yet to identify a functional graft that is capable of addressing the various biological issues necessary to maintain long term patency for these applications.
For example, cardiovascular disease, including coronary artery and peripheral vascular disease, is typically treated by surgical replacement. With around 8 million people with peripheral artery disease, 500,000 patients diagnosed with end-stage renal disease, and 250,000 patients undergoing coronary bypass surgeries each year in the United States alone, there is a significant demand for luminal grafts in vascular surgery. This is especially true with respect to functional small-caliber blood vessels (<4 mm in diameter).
Despite this clear clinical need for a functional small-diameter vessel graft, replacement therapy with respect to small-diameter blood vessels has been met with limited success. One reason or this is that the application of conventional methods for creating replacements for large-caliber vessels have generally proved inadequate when applied to small-caliber vessel substitutes. For example, while artificial, biological and modulated materials (including, without limitation, synthetic polymer scaffolds (polyurethane), synthetic scaffolds treated with biological molecules such as collagen, heparin, laminin, anti-coagulant peptides, etc.) have proven successful with respect to large-caliber vessel grafts, these materials are not particularly suited for creating small-diameter luminal grafts. This is due, at least in part, to the lower blood flow velocities of smaller vessels, which require a different set of design criteria and introduce a host of new problems not encountered in large-caliber vessel substitutes. Indeed, in low-flow situations, synthetic and other conventional grafts are prone to sudden thrombosis and provoking a wound-healing response from adjacent vessels and the surrounding tissue that under some circumstances narrows the lumen and reduces blood flow therethrough. Accordingly, when conventional materials are used to prepare small-diameter vessel grafts, the replacement grafts' have shown an increased tendency (a) for thrombogenicity; (b) to develop embolism and/or occlusion of the graft lumen (i.e. intimal hyperplasia and negative remodeling); (c) to develop anastomotic intimal hyperplasia; (d) for aneurysm formation of the graft itself; and/or (e) to cause a compliance mismatch with the host vessel.
For these reasons, operations using autologous vessels remain the standard for small-diameter grafts. However, there are also issues associated with this approach. Many patients do not have a vessel suitable for use because of vascular disease, amputation, or previous harvest, and this method requires a second complicated surgical procedure to obtain the vessel. As a result, there is a demand for a vascular prosthesis which is suited to the small-diameter blood vessels.
Recently, tissue engineering has emerged as an alternative approach to address the shortcomings of current options. Specifically, decellularized scaffolds (decellularized artery, vein and/or other suitable tissue) have been made by removing the cellular components of the tissue, thereby resulting in a decellularized scaffold that is entirely comprised of natural extracellular matrix. After the decellularized scaffold is formed, the same is recellularized by host cells. For example, the scaffolds may host smooth muscle cells and fibroblasts that mimic native blood vessels. Purified proteins have also been used to form scaffolds of such tubular constructs.
Preparation of the scaffolds typically requires a few months (about three months) for the native smooth muscle and fibroblasts to seed on the scaffold for inhibition of immunoreactions before implantation. Due to the composition of such decellularized scaffolds, the scaffolds retain beneficial native mechanical properties, promote regeneration and exhibit favorable biocompatibility. While over the last decade, cardiovascular tissue engineering has experienced a dramatic paradigm shift from biomaterial-focused approaches and towards the more biology-driven strategies, there currently remains no functional vessel graft that has addressed the various biological issues necessary to maintain long term patency.
B. Hemodialysis
It has been estimated that, globally, approximately 8.3% of adults have diabetes and the number of people with diabetes is set to rise beyond 592 million by 2025. Further, according to recent projections, 53.1 million Americans will have diabetes in the year 2025 (diagnosed and undiagnosed), representing a 63% increase from the number of Americans with diabetes today. As may be expected, the burden of cardiovascular disease and premature mortality that is associated with diabetes will also substantially increase, reflecting not only an increased amount of individuals with coronary artery disease, but an increased number of younger adults and adolescents with type 2 diabetes who are at a two- to four-fold higher risk of experiencing a cardiovascular-related death as compared to non-diabetics. Accordingly, aside from promoting awareness and prevention of the disease, there is a vast need to facilitate both treatment and cost efficacy in the treatment of those afflicted with the chronic disorder.
Adults with diabetes or high blood pressure (or both) have an increased risk of developing chronic kidney disease (CKD). It has been estimated that more than 20 million Americans have CKD, including approximately 1 of 3 adults with diabetes and 1 of 5 adults with high blood pressure. Other risk factors for CKD include cardiovascular disease, obesity, high cholesterol, lupus, and a family history of CKD. While some of these patients undergo treatment to maintain some kidney functions, some patients lose their kidney function altogether, which is referred to as end-stage renal disease (ESRD). As the kidneys are responsible for filtering out waste products from the blood, patients with ESRD require either dialysis or a kidney transplant to survive. Conventionally, three-times weekly, in-center dialysis is the most commonly performed modality.
In 2012, it was estimated that around 398,000 Americans relied on some form of dialysis to keep them alive. Needless to say, the cost associated with providing such procedure is considerable. A significant portion of the total cost is spent on hemodialysis vascular access, which has been long considered to be the most problematic part of dialysis. There are three basic kinds of vascular access for hemodialysis: 1) ateriovenous (AV) fistula; 2) an AV graft; or 3) a venous catheter. Hemodialysis patients who do not have adequate veins for a fistula become candidates for an AV graft or a venous catheter. Conventional AV grafts and venous catheters are typically discouraged due to their high morbidity and mortality. Specifically, such types of vascular access tend to have more problems than fistulas with respect to clotting and infection.
An AV graft is created by connecting an artery to a vein with a synthetic tube of biocompatible material (i.e. the graft), and implanting the same subcutaneously. The graft then functions as an artificial vein that can be used repeatedly for needle placement and blood access. One problem associated with this technique is that thrombosis of the graft is common, which can develop due to poor blood flow. Another risk relates to an increased risk in the development of vascular access steal syndrome, which refers to vascular insufficiency resulting from the AV graft. Considering the limitations of conventional AV grafts and the prevalence of hemodialysis in the United States alone, a need exists for an improved design. Accordingly, it would be desirable to have a vessel graft that is capable of long term patency and does not increase the risk of aneurysm.
C. Nerve Regeneration
Nerve injuries are common in clinical practice. While the central nervous system is, for the most part, incapable of self-repair and regeneration, the peripheral nervous system (PNS) has the intrinsic ability to repair and regenerate. Specifically, nerve fiber regeneration is due to the growth of transected axons of the nerve stump proximal to the lesion and not to a regenerative process of axons of the distal stump. However, even PNS nerve regeneration is a complex biological phenomenon and does not occur spontaneously without treatment. Furthermore, nerves in the PNS can regenerate only under certain circumstances—for example, if the injuries are limited to a small enough portion of the nerve length.
Historically, the common surgical approach to repairing a transected nerve has been direct suture of the two stumps when the ends can be approximated without tension. However, this technique is difficult, time-consuming and often yields poor functional results. Furthermore, where nerve substance loss occurs (i.e. the defect is longer), a neurorrhaphy without tension at the site of repair cannot be performed. For more extensive peripheral nerve injuries/lesions (e.g., where the nerve defect gap is longer than, for example, about 20 mm) the surgical repair of nerve gap has conventionally been achieved using autologous nerve grafts. In such cases, a nerve graft is typically used to bridge the two stumps or ends and promote nerve regeneration, rather than suturing the two stumps under tension. However, there are significant disadvantages to autologous nerve grafting as it requires an extra incision for the withdrawal of a healthy nerve (which could also result in sensory residual deficits) and, often, the length of the graft material is limited. Currently, biomedical strategies for PNS regeneration focus on developing alternative treatments to nerve grafting (e.g., nerve guidance channels or tubulization), whereas efforts for spinal cord injury are focused on creating a permissive environment for regeneration. Unfortunately, a solution to completely repair long spinal cord injuries has not yet been identified.
Sutureless tubulization techniques provide an alternative to direct nerve sutures and nerve grafting. Tubulization involves forming non-nervous luminal grafts (e.g., venous or arterial conduit grafts) to create optimal conditions for nerve regeneration over the empty space intentionally left between two nerve stumps. Nevertheless, such alternatives have not shown substantial benefits compared with standard nerve grafts.
In order to achieve a better clinical outcome, various materials (both biological and synthetic) have been studied in connection with tubulization. Enriching the graft tubes with other tissue (e.g., pieces of nerve or skeletal muscle to form a “biological” graft) has seen some success when used in tubulization applications, however, only with limited efficacy—functional recovery has only been achieved for injured gaps shorter than about 4 cm for both sensory and mixed nerves. Alternatively, non-biological synthetic materials have also been employed, albeit also with limited success. When nonabsorbable synthetic grafts are used in humans, the occurrence of complications due to local fibrosis (triggered by the implant material) and nerve compression becomes a substantial concern. This is due, at least in part, to the graft's non-degradable nature and its inability to adapt to the nerve growth and maturation. As such, synthetic nerve repair conduits used for bridging strategies have increasingly been made of biodegradable or bioresorbable materials. Among these, polyglycolic acid nerve repair conduits are an example of one biodegradable material that has shown a decreased prevalence of complications as compared to non-absorbable synthetic materials. However, even such bioabsorbable/bioresorbable nerve conduits have flaws and the results thus far are still not satisfactory.
Finally, nerve reconstruction by tissue engineering has seen an increased interest in recent years. In tissue engineering, two concepts have guided the development of recent nerve regeneration technologies: 1) the manipulation of tissues and organs in vitro to fashion conduit should attempt to mimic important features of the nerve environment; and 2) various elements considered essential for promoting nerve fiber regeneration are missing in non-nerve grafts and, as such, an attempt should be made to enrich biological or synthetic tubes with the same. However, currently, despite the ongoing research and working concepts, conventional conduits (whether formed by tissue engineering or otherwise) continue to fall short and exhibit critical flaws. Accordingly, it would be desirable to have a luminal graft that satisfies all of the biological requirements necessary for the successful promotion of peripheral nerve regeneration.